Treatment of cancer with targeted fusion proteins has shown much promise, but many problems remain. For example, antibody-targeted cytokines have shown much promise in the treatment of cancer in animal models and in some human studies, but the optimal choice of antibody/antigen, cytokine, and antibody effector function remains to be determined. For example, Gillies (U.S. Pat. No. 5,650,150) described the general usefulness of cytokine fusions to complete antibodies, and the specific usefulness of antibody-IL2 fusion proteins.
Interleukin-12 (IL-12) is a particularly attractive cytokine for targeted immune therapy, because IL-12 stimulates a Th1 immune response, which is most effective in attacking tumour cells. IL-12 is quite toxic when administered systemically, consequently it is particularly important to direct its activity to a tumour site. Gillies et al. (WO 99/29732) described the usefulness of fusions of IL-12 to antibodies and also described particular techniques needed to express IL-12 fusion proteins, relating to the fact that IL-12 is a two-subunit cytokine in which one of the subunits can homodimerise. Halin et al., 2002, Nature Biotechnology 20:264-269 described a fusion protein consisting of a single-chain IL-12 moiety fused to a single-chain Fv (sFv) with the variable domains of L19, an antibody that binds to tumour-specific neovasculature. This latter molecule lacks the Fc region of the antibody and thus lacks all effector functions.
Even when IL-12 is fused to a targeting moiety, there is a period after the fusion protein is administered when the protein drug circulates systemically. During this period and before the drug accumulates in the tumour and disappears from the rest of the system, secondary cytokines are induced and damage results.
Hence, there is a need for improved means of delivering IL-12 to a tumour site within a patient.